ORIGINAL ARTICLE
Formulation Dependent Pharmacokinetics—
Does the Dosage Form Matter for Nifedipine?
Corey B. Toal, BSc, MSc, PhD
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Abstract: This was an open-label, randomized, 3-way crossover
study that compared in 25 healthy male subjects, the pharmacokinet-
ics of a single 60-mg dose of nifedipine GITS tablet versus (1) 20-mg
doses of nifedipine prolonged action tablets given q12h for a total of
two doses and (2) 2 × 10 mg doses of nifedipine capsules given q8h
for a total of three doses. Following capsule administration, there was
a rapid rise in plasma concentration of drug achieving a peak concen-
tration of 196(35) ng/mL (mean and coefficient of variation) within
0.7 (105) hours and an AUC⬁ of 973(39) ng.hr/mL. After nifedipine
PA there was also a rapid rise in plasma concentration of drug achiev-
ing a Cmax of 85.5 (36) ng/mL with a tmax of 1.7(58) hours and an
AUC⬁ of 879(46) ng.hr/mL. For the nifedipine GITS formulation,
there was a lag in the plasma concentration time profile for approxi-
mately 2 to 3 hours, then it rose gradually achieving a Cmax of
30.5(63)ng/mL with a tmax of 15.0(50) hours and an AUC⬁ of 686(54)
ng.hr/mL. The AUC⬁ and Cmax were significantly (P = 0.0001)
greater in the capsule and PA formulations than for the GITS; how-
ever, the tmax for the GITS formulation was significantly (P = 0.001)
longer than for the other formulations.
This study suggests marked formulation-dependent pharmaco-
kinetics, which may have important clinical implications.
Key Words: calcium channel antagonists, pharmacokinetics, nifed-
ipine
(J Cardiovasc Pharmacol™ 2004;44:82–86)
N ifedipine is the prototype calcium channel blocker of the
dihydropyridine class. It is available in various formula-
tions worldwide for the management of hypertension and an-
gina pectoris. The capsule was the first formulation available
for clinical use, which contained drug in solution with peak
plasma concentration achieved within 1 to 2 hours and a rela-
tively short terminal half-life of 2 hours.1,2 As a consequence,
repeated doses at 8-hourly intervals was required to maintain
therapeutic plasma concentrations but due to its rapid onset of
Received for publication December 19, 2003; accepted March 17, 2004.
From the Department of Pharmacology, University of Toronto and Bayer Inc.,
Toronto, Canada.
This study was funded by Bayer Inc.
Reprints: Corey B. Toal, Bayer Inc., 77 Belfield Road, Toronto, Ontario,
Canada M9W 1G6 (e-mail: corey.toal.b@bayer.com).
Copyright © 2004 by Lippincott Williams & Wilkins
82
action, short half-life, and side effect profile the need for fur-
ther pharmaceutical development was apparent.
The subsequent formulation of nifedipine was a pro-
longed action or retard tablet, which contained nifedipine par-
ticles of differing surface area. Absorption from this tablet
form of nifedipine was determined by dissolution rate of the
nifedipine particles with peak plasma concentrations occurring
after 4 hours and declining with a half-life of 11 hours.2 How-
ever, both the capsule and prolonged action formulation both
resulted in a rapid drop in blood pressure in patients3 and reflex
activation of the sympathetic nervous system.2–4 An extended
release formulation, Gastro-Intestinal Therapeutic System
(GITS), was developed,5 which is based on osmotic push-pull
technology. The tablet consists of a 2-layer core of nifedipine
and osmotic polymer surrounded by a semi permeable mem-
brane. The membrane contains a small laser-drilled hole.
When swallowed, the tablet absorbs water from the gut
through the semi-permeable membrane. The nifedipine-
containing core layer forms a suspension, which is then pushed
out of the laser-drilled hole at a constant rate by the expansion
of the polymer core layer. The GITS formulation delivers drug
at a constant rate for approximately 16 to 18 hours6 thus allow-
ing once daily dosing. Clinically, the GITS formulation is ef-
ficacious for treating hypertension7,8 and angina pectoris9,10
once daily.
To compare the pharmacokinetics of these 3 different
formulations the following study was conducted.
METHODS
Study Design
This was an open-label, randomized, 3-way crossover
study to compare the pharmacokinetics of a single 60-mg dose
of nifedipine GITS tablet (Adalat® XL®) versus (1) 20-mg
doses of nifedipine prolonged action (PA) tablets (Adalat
®PA) given q12h for a total of 2 doses and (2) 2 × 10 mg doses
of nifedipine capsules (Adalat®) given q8h for a total of 3
doses. Each treatment period was separated by a 6-day wash-
out interval. Before the initiation of any study procedures, an
institutional review board approved the protocol.
Thirty healthy male volunteer subjects, between 18 and
45 years of age and within 15% of their ideal body weight,
were enrolled in this study after giving written informed con-
J Cardiovasc Pharmacol姠 • Volume 44, Number 1, July 2004
J Cardiovasc Pharmacol姠 • Volume 44, Number 1, July 2004
sent. Eligible study candidates had clinically normal labora-
tory profiles of hematopoietic, hepatic, and renal functions and
normal electrocardiograms. Subjects were excluded from
study participation if there was a medical history or evidence
of cardiovascular, hepatic, renal, hematological, or gastroin-
testinal disorder, alcoholism or drug abuse, or if they had par-
ticipated in another clinical trial within 28 days of the current
study. Subjects had not received medication during the 7 days
preceding the study and the consumption of alcohol or xan-
thine-containing food or beverages was prohibited for 24 hours
before study dosing and throughout the study period.
Subjects were housed from 12 hours before dosing until
after the 36-hour blood draw for the nifedipine PA tablet and
nifedipine capsule administration periods and until after the
48-hour blood draw for the nifedipine GITS tablet administra-
tion period. All subjects fasted under supervision for at least
12 hours before the initial dose, for 4 hours before all subse-
quent doses, and for 4 hours after all doses. For all treatment
periods, standard identical meals were provided 4 and 8 hours
after initial dosing during the nifedipine GITS and nifedipine
PA periods and at 4 and 12 hours after initial dosing in the
nifedipine capsule administration period. All study medica-
tions were administered orally with 240 mL of water at ambi-
ent temperature.
Blood specimens were collected via an indwelling intra-
venous catheter (heparin lock), which was inserted into the
arm before initial dosing. Blood specimens were collected at
specified times up to 36 hours after the initial doses of nifed-
ipine PA and nifedipine capsule and up to 48 hours after the
single dose of nifedipine GITS. Samples were cooled in an ice
bath and centrifuged under refrigeration as soon as possible
after collection. Plasma samples were divided into 2 portions
and stored frozen at −12°C. Due to the sensitivity of nifedipine
to UV light, blood samples were collected and processed under
conditions where UV exposure was minimized.
Subjects were to engage in normal activity for the first
4 hours after daytime drug administration and were to avoid
vigorous exertion and complete rest. As a general measure of
safety, heart rate and sitting blood pressure were determined
before dosing and at the following times thereafter: 2, 4, 8, 12,
16, and 24 hours. Mean arterial pressure was calculated as the
diastolic pressure plus one third of the pulse pressure. Subjects
were monitored throughout each period for the appearance of
adverse events by a blinded evaluator.
Analytical Procedures
Plasma samples collected during each treatment period
were assayed by gas chromatography with electron-capture
detection. The assay was linear and reproducible in the con-
centration range of 0.5 to 200 ng/mL. Samples with drug con-
centrations greater than the upper end of the validated linear
range of the assay were diluted with appropriate drug-free bio-
logic fluid and re-assayed. Standard and quality control
© 2004 Lippincott Williams & Wilkins
Formulation Dependent Pharmacokinetics of Nifedipine
samples were distributed in each batch of assayed samples.
The batch acceptance criteria for the quality control samples
ranged from within 10% of the theoretical concentration for
samples containing 3 to 5 times the lower limit of quantitation
to within 20% for samples containing 80 to 90% of the upper
limit of quantitation.
Pharmacokinetic and Statistical Analyses
The areas under the time concentration curves (AUC)
were calculated by the trapezoidal rule and extrapolated to in-
finity (AUC⬁) by adding the quantity equal to the last measur-
able concentration divided by the elimination rate constant.
Cmax is defined as the maximum measured plasma concentra-
tion over the time span specified and tmax, the time to Cmax. Where
tmax occurred at more than 1 time point, the first time point with
this value was taken as tmax. The apparent first-order elimina-
tion rate constant (kel) was calculated from a log-linear plot of
the last 3 (or more) non-zero concentrations in the plasma con-
centration versus time curve.
Adjustments for formulation dosage were conducted for
the calculation of AUC and Cmax for the 20 mg nifedipine PA
formulation (2 doses). Data were normalized to the 60-mg
dose level of the other 2 formulations by multiplying by 1.5.
Three-way analyses of variance with subject, period, and drug
formulation as factors, and sequence as a between-subject
factor, were applied to ln AUC⬁ ln Cmax, tmax and kel. For ln-
transformed data, mean ratios were calculated using the equa-
tion: ratio = elnA-lnB × 100.
RESULTS
Study Subjects
Twenty-five of the thirty subjects completed all 3 treat-
ment periods according to the study protocol and were in-
cluded in the analyses of pharmacokinetic data. Five subjects
failed to complete all 3 treatment periods and were included in
the safety analysis only. Demographic characteristics of all
study subjects (mean ± standard deviation) were as follows:
age 30 ± 6.5 years, height 174 ± 5.6 cm, weight 73.7 ± 8.6 kg.
Baseline blood pressure was 115 ± 9/71 ± 6 mm Hg on cap-
sules, 116 ± 12/70 ± 8 mm Hg on prolonged action, and 118 ±
11/71 ± 8 mm Hg on nifedipine GITS. The respective baseline
heart rates were 71 ± 7, 70 ± 7, and 70 ± 7 beats per minute.
Pharmacokinetic Parameters
Mean plasma nifedipine concentration for each nifed-
ipine formulation under fasting conditions is presented in the
linear plot in Figure 1. The mean plasma concentration-time
profiles differ significantly for each of the 3 formulations of
nifedipine. Following each administration of the capsule for-
mulation, there was a rapid rise in plasma concentration of
drug achieving peak concentration in excess of 80 ng/ml each
time within 1 hour of administration. Moreover, within 8 hours
83
Toal J Cardiovasc Pharmacol姠 • Volume 44, Number 1, July 2004

FIGURE 1. Mean plasma nifedipine concentrations in

25 healthy adult volunteer subjects following the ad-
ministration of the capsule formulation (open
circles), the PA formulation (open triangles), or the
GITS formulation (open squares).

of each dose, the plasma concentrations had declined to less
than 15 ng/ml. After the administration of the prolonged action
formulation, there was a rapid rise in plasma concentration
achieving peak concentration in excess of 40 ng/ml within
2 hours after each dose. The decline in plasma concentration of
nifedipine was also relatively quick reaching less than 7 ng/ml
within the 12-hour dosing interval. Following the administra-
tion of the GITS formulation, there is a lag in the increase in the
nifedipine plasma concentration time profile for approxi-
mately 2 to 3 hours after which the curve increases gradually to
approximately 6 hours and thereafter remains relatively con-
stant beyond 24 hours. The mean estimates and coefficients of
variation of the major pharmacokinetic parameters are pre-
sented in Table 1. The evaluations resulted in mean AUC(0-⬁)
for the capsules and prolonged action tablet of 973 ng.hr/mL
and 879 ng.hr/mL respectively, which show a higher extent of
nifedipine bioavailability than the GITS formulation, 686
ng.hr/mL. The Cmax calculations of the capsule and prolonged
action formulation of 196 ng/mL and 85.5 ng/mL were also
significantly greater than for the GITS formulation 30.5
ng/mL. The Cmax of the GITS concentration curve is approxi-
mately 36% and 16% of the Cmax for the PA and the nifedipine
capsule formulations, respectively. Following nifedipine cap-
sule administration the mean tmax was 0.7 hours and 1.7 hours
for the prolonged action tablet. By contrast the nifedipine
GITS tablet tmax was significantly longer at 15.0 hours.
Safety
Five subjects did not complete all 3 treatment periods
of the study; 3 subjects discontinued due to personal reasons,
1 subject discontinued due to low hemoglobin, and 1 subject
discontinued during the GITS administration period due to ad-
verse events of hot/cold sensation, headache, vomiting, diar-
rhea, and chest pains. The effects of each formulation of drug
on mean arterial pressure and heart rate is shown in Figure 2.
There did not appear to be any marked changes in heart rate
related to changes in blood pressure, on any of the formula-
tions of nifedipine in these healthy subjects. The summary of
all adverse events experienced by study subjects is presented in
Table 2. In terms of total events, there appeared to be more on

TABLE 1. Pharmacokinetic Parameters of Nifedipine Following Oral Administration of the

GITS Tablet, Prolonged Action (PA) Tablet, or Capsule Formulations in 25 Healthy
Volunteer Subjects

Nifedipine AUCⴥ ln AUCⴥ Cmax ln Cmax tmax

Formulation ng ⴢ hr/mL ng ⴢ hr/mL ng/mL ng/mL hr Kel/hr
GITS 686 (54) 6.4 30.5 (63) 3.3 15.0 (50) 0.14 (39)
PA 879 (46) 6.7* 85.5 (36) 4.4* 1.7 (58)† 0.20 (19)*
Capsule 973 (39) 6.8* 196 (35) 5.2* 0.7 (105)† 0.21 (26)*
Ratio
PA:GITS 128 132 280 297
Capsule:GITS 142 151 626 682
Results are expressed as mean (coefficient of variation = SD ÷ mean × 100).
AUC⬁ and Cmax data were normalized to the 60-mg dose level.
3-way analysis of variance: *P = 0.0001 PA > GITS, Capsule > GITS
†P = 0.001 PA < GITS, Capsule < GITS

84 © 2004 Lippincott Williams & Wilkins

J Cardiovasc Pharmacol姠 • Volume 44, Number 1, July 2004 Formulation Dependent Pharmacokinetics of Nifedipine

FIGURE 2. Mean arterial pressure and heart rate in

25 healthy adult volunteer subjects following the ad-
ministration of the capsule formulation (diamonds
and solid lines), the PA formulation (squares and bro-
ken line), or the GITS formulation (triangles and dot-
ted line). The mean arterial pressure data is shown in
the top part of the panel with filled symbols and the
heart rate data is displayed in the bottom part of the
panel with open symbols.

the short-acting prolonged action and capsule formulation of hours after dosing, which is similar to the three 20 mg PA tab-
nifedipine compared with nifedipine GITS but no formal sta- lets administered in the study of Banzet et al,4 which achieved
tistical evaluation was performed. The most frequently re- a Cmax of 170.1 ng/ml at 1.75 hours. After a 60-mg dose of
ported event was headache and all adverse events were mild or nifedipine GITS there is a slower rise in plasma concentration
moderate in intensity. Clinical laboratory evaluation was com- with a Cmax of 30.5 ng/ml being achieved at 15.0 hours. More-
pleted only as part of the pre-study subject screening. over, this formulation exhibits a reasonably consistent plasma
concentration over 24 hours. These results are in the same
DISCUSSION range as the previous results with 60 mg given under fasting
Nifedipine has existed in a number of different immedi- conditions with tmax at approximately 6 hours6; Cmax 31 ng/mL
ate release and modified release formulations since its general at a tmax of 10 hours11; Cmax 23.2 ng/mL at a tmax of 9 hours.12
availability in the early 1980s but no previous study has com- Although this study was not designed to systematically
pared the pharmacokinetics of the capsule, retard (PA), and assess blood pressure and heart rate, both these parameters
GITS formulations in a single study. In the present study, the were measured once in subjects at predefined time points while
capsule formulation exhibits a rapid rise in plasma concentra- on each drug formulation. There was no apparent relationship
tion achieving a Cmax of 196 ng/ml within 0.7 hours. These between peak plasma concentration of drug on repeated dosing
results are consistent with earlier reports3 in an older (mean 63 of the 2 short-acting formulations (capsule and PA) and blood
years) group of hypertensives and in healthy subjects.2 The pressure lowering. There was also a lack of relationship be-
results obtained with the nifedipine retard tablet are more dif- tween peak concentration of nifedipine GITS and blood pres-
ficult to compare with previous studies since the data are nor- sure. These data are in contrast to a number of studies, which
malized to the 60-mg dose for comparison purposes within the have shown that blood pressure response is highly correlated to
study. A corrected Cmax of 85.5 ng/ml was obtained at 1.7 plasma concentration.2–4,13 This may be related to the fact that
healthy adult volunteers with baseline blood pressures in the
normal range (ie, 116/70 mm Hg) were the subjects or more
TABLE 2. Adverse Events Reported by at Least 2 Study likely that measurements of blood pressure and heart rate were
Subjects During the Administration of Nifedipine GITS not conducted frequently enough to pick up changes.
Tablet, Nifedipine Prolonged Action (PA) Tablet, or This study, as in previous ones, demonstrates the marked
Nifedipine Capsule
variability in plasma concentration time profiles of nifedipine
GITS PA Capsule administered in its various formulations after a single dose un-
(n = 29) (n = 26) (n = 29) der fasting conditions. It is certainly plausible due to the effects
Adverse Event n (%) n (%) n (%) of nifedipine on the vascular smooth muscle and subsequent
Any adverse event 7 (24) 9 (35) 11 (38) blood flow for example to the liver that nifedipine could alter
Headache 6 (21) 9 (35) 9 (31) its own metabolism.14,15
Dizziness 1 (3) 1 (4) 2 (7) However, the intraindividual variability is smaller
Vomiting 2 (7) 0 (0) 0 (0) (13%) than the interindividual variability (54%).13 Another
Nausea 1 (3) 1 (4) 1 (3) factor leading to marked variability in plasma concentration
Other 6 (21) 0 (0) 4 (14) time profile is the concomitant administration of food in for-
n = number of subjects.
mulations dependent on erosive modified release matrixes. For
example, with nifedipine PA a high fat meal significantly in-

© 2004 Lippincott Williams & Wilkins 85

Toal
creased the Cmax from 36.8 µg/ml to 58.9 µg/ml.16 In a once
daily hydrophilic matrix tablet of nifedipine food significantly
increased the Cmax from 34 ng/mL to 137 ng/mL.17 Recently
two other once daily formulations of nifedipine (Nifedicron,11;
Coral,12) exhibited significant increases in Cmax and shifts to
shorter tmax relative to the reference nifedipine GITS formula-
tion. The clinical implications of these marked differences in
pharmacokinetics between formulations must be considered
when administering them to patients since the blood pressure
response has been shown to be highly correlated to plasma ni-
fedipine concentration.2–4,13
Moreover, just measuring blood pressure at one instant
in a 24-hour period may not provide accurate information as to
the physiologic effect of the drug formulation since the peak
plasma concentration of drug may be missed and hence the
effect on blood pressure. In addition, the different immediate
release capsule and modified release PA formulations have
been shown to result in a reflex activation of the sympathetic
nervous system (heart rate and plasma norepinephrine in-
crease) at the time of peak plasma drug concentration, which
correlates to maximum blood pressure decrease.2,18 Recent re-
ports from South Africa suggest that switching between for-
mulations is not optimal since potential manifestations of the
activation of the sympathetic nervous system such as acute
coronary and cerebrovascular events have been reported.19
CONCLUSION
The present study demonstrates the marked formulation-
dependent pharmacokinetics of nifedipine with the GITS for-
mulation showing the least fluctuation of nifedipine in 24-hour
plasma concentration time profile. The clinical implications of
the differences between formulations are important for prac-
ticing physicians when considering changes in their patients’
medication.
ACKNOWLEDGMENTS
The author acknowledges the excellent work of Phoenix
International Life Sciences (Montreal), who carried out the
clinical parts of this study.
REFERENCES
1. Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifed-
ipine. Hypertension. 1983;5(Suppl 2):18–24.
86
J Cardiovasc Pharmacol姠 • Volume 44, Number 1, July 2004
2. Kleinbloesem CH, van Brummelen P, van de Linde JA, et al. Nifedipine
kinetics and dynamics in healthy subjects. Clin Pharmacol Ther. 1984;
35:742–749.
3. Myers MG, Raemsch KD, et al. Comparative pharmacokinetics and anti-
hypertensive effects of the nifedipine tablet and capsule. J Cardiovasc
Pharmacol. 1987;10:S76–S78.
4. Banzet O, Colin JN, Thibonnier M, et al. Acute antihypertensive effect
and pharmacokinetics of a tablet preparation of nifedipine. Eur J Clin
Pharmacol. 1983;24:145–150.
5. Swanson DR, Barclay BL, Wong P, et al. Nifedipine gastrointestinal
therapeutic system. Am J Med. 1987;83:3–9.
6. Chung M, Retiberg DP, Godfrey M, et al. Clinical pharmacokinetics of
nifedipine gastrointestinal system. Am J Med. 1987;83:10–14.
7. Krakoff LR, Bravo EL, Tuck ML, et al. Nifedipine gastrointestinal thera-
peutic system in the treatment of hypertension. Results of a multicenter
trial. Am J Hypertens. 1990;3:318S–325S.
8. Toal C. Efficacy of a low dose nifedipine GITS (20 mg) in patients with
mild to moderate hypertension. Can J Cardiol. 1997;13:921–927.
9. Walker JM, Curry PVL, Bailey AE, et al. A comparison of nifedipine once
daily (Adalat LA), isosorbide mononitrate once daily, and isosorbide di-
nitrate twice daily in patients with chronic stable angina. Int J Cardiol.
1996;53:117–126.
10. Toal CB, Motro M, Baird MG, et al. Effectiveness of nifedipine GITS in
combination with atenolol in chronic stable angina. Can J Cardiol. 1999;
15:1103–1109.
11. Schug BS, Brendel E, Winneman M, et al. Dosage form-related food
interaction observed in a marketed once-daily nifedipine formulation
after a high-fat American breakfast. Eur J Clin Pharmacol. 2002;58:119–
125.
12. Schug BS, Brendel E, Wolf D, et al. Formulation-dependent food effects
demonstrated for nifedipine modified-release preparations marketed in
the European Union. Eur J Clin Pharmacol. 2002;15:279–285.
13. Soons PA, Schoemaker HC, Cohen AF, et al. Intraindividual variability in
nifedipine pharmacokinetics and effects in healthy subjects. J Clin Phar-
macol. 1992;32:324–331.
14. Bauer LA, Murray K, Horn JR, et al. Influence of nifedipine therapy on
indocyanine green and oral propanolol pharmacokinetics. Eur J Clin
Pharmacol. 1989;37:257–260.
15. Soons PA, Kroon JM, Breimar DD, et al. Effects of single-dose and short-
term oral nifedipine on indocyanine green clearance as assessed by spec-
trophotometry and high performance liquid chromatography. J Clin Phar-
macol. 1990;30:693–698.
16. Armstrong J, Challenor VF, Macklin BS, et al. The influence of two types
of meal on the pharmacokinetics of a modified-release formulation of ni-
fedipine (Adalat Retard). Eur J Clin Pharmacol. 1997;53:141–143.
17. Abrahamsson B, Alpsten M, Bake B, et al. Drug absorption from nifed-
ipine hydrophilic matrix-extended release (ER) tablet-comparison with
an osmotic pump tablet and effect of food. J Control Rel. 1998;52:301–
310.
18. de Champlain J, Karas M, Nguyen P, et al. Different effects of nifedipine
and amlodipine on circulating catecholamine levels in essential hyperten-
sive patients. J Hypertens. 1998;16:1357–1369.
19. Rayner B, Buchanan-Lee B, Brink J, et al. Generic substitution—Is it safe
in patients at high cardiovascular risk? S Afr Med J. 2002;92:603–604.
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